Registration Dossier

Administrative data

Description of key information

None of the category members of the PFAE fumarate group is considered to be skin or eye irritating.

Key value for chemical safety assessment

Skin irritation / corrosion

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Eye irritation

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for grouping of substances and read-across

The PFAE fumarates (Polyfunctional Aliphatic Ester) category consists of seven members, which are either well-defined mono-constituent substances or related UVCB substances, with varying fatty alcohol chain lengths. The distinguishing feature of this category of chemicals is that its members are diester derivatives of fumaric acid (CAS 110-17-8). The alcohol moiety of the dicarboxylic esters generally falls in the C12-C22 carbon number range, including linear, even and odd numbered alcohols. 

In order to avoid the need to test every substance for every endpoint, the category concept is applied for the assessment of environmental fate, environmental toxicity and human health hazards. Thus where applicable, environmental and human health effects are predicted from adequate and reliable data for source substance(s) within the group by inter- or extrapolation to the target substances in the group (read-across approach) applying the group concept in accordance with Annex XI, Item 1.5, of Regulation (EC) No 1907/2006. Structural similarities and similarities in properties and/or activities of the source and target substances in the category are the basis of read-across.

The available studies providing information on the human health hazard assessment within the PFAE fumarates category were conducted with the category member Didodecyl fumarate (CAS 2402-58-6). This substance represents the category member with the shortest fatty alcohol side chain, and consequently with the lowest molecular weight, which is regarded as worst-case approach in terms of hazard assessment of the PFAE fumarates for the local as well as for systemic effects. Additionally, experimental data is available from the category member Di-C12-15 Alkyl Fumarate.

Furthermore, the category is supported by another polyfunctional aliphatic ester, namely Bis(2-ethylhexyl) adipate (CAS 103-23-1). This supporting chemical is used to cover toxicological endpoints, exclusively. The read across of Bis(2-ethylhexyl) adipate (CAS 103-23-1) to the PFAE fumarate category is justified due to the similar structural and physico-chemical properties, as well as their toxicological, and ecotoxicological profiles.

A detailed justification for the grouping of chemicals and read-across is provided in the technical dossier (see IUCLID Sections 7.1 and 13) and within Chapter 5.1 of the CSR.

Endpoint specific data matrix:

ID #

CAS

Skin irritation/corrosion

Eye irritation

1

2402-58-6

Experimental result: Not irritating

Experimental result: Not irritating

2

10341-03-4

RA: CAS 2402-58-6

RA: CAS 2402-58-6

3

no CAS / List No. 938-575-3

RA: CAS 2402-58-6

RA: Di-C12-15 Alkyl Fumarate

RA: CAS 2402-58-6

RA: Di-C12-15 Alkyl Fumarate

4

no CAS / Di-C12-15 Alkyl Fumarate

Experimental result: Not irritating

Experimental result: Not irritating

5

no CAS / List No. 938-576-9

RA: CAS 2402-58-6

RA: Di-C12-15 Alkyl Fumarate

RA: CAS 2402-58-6

RA: Di-C12-15 Alkyl Fumarate

6

1187576-41-5

RA: CAS 2402-58-6

RA: Di-C12-15 Alkyl Fumarate

RA: CAS 2402-58-6

RA: Di-C12-15 Alkyl Fumarate

7

68921-53-9

RA: CAS 2402-58-6

RA: CAS 2402-58-6

 

Discussion:

CAS 2402-58-6

Skin irritation:

The potential of Didodecyl fumarate (CAS 2402-58-6) to cause dermal irritation was assessed by a single topical application of 25 µL bulk volume (about 15 mg) of the undiluted test substance to a reconstructed three dimensional human epidermis model according to OECD 439 (Remmele, 2013). Three EpiDerm TM tissue samples were incubated with the test substance for 1 hour followed by a 42-hour post-incubation period. Tissue destruction was determined by measuring the reduction of mitochondrial dehydrogenase activity, indicated by reduced formazan production after incubation with a tetrazolium salt (MTT).The formazan production after incubation with a substance treated epidermal tissues is compared to that of negative control tissues. The quotient of both values indicates the relative tissue viability. The EpiDerm TM skin irritation test showed the following results: The test substance is not able to reduce MTT directly. The mean viability of the test substance treated tissues determined after an exposure period of 1 hour and after 42 hours post-exposure was 96%. Based on the observed results and applying the evaluation criteria it was concluded, that the test substance does not show skin irritation potential in the EpiDerm TM skin irritation test under the test conditions chosen.

Di-C12-15 Alkyl Fumarate

The potential of Di-C12-15 Alkyl Fumarate to cause dermal irritation was assessed in a study similar to OECD guideline 404 (Cantor, 1991). Six New Zealand White Rabbits were treated on the clipped skin (abraded and non-abraded) with 0.5 mL of the test material under occlusive conditions for a exposure period of 24 h. Untreated skin sites of the same animal served as the control. The treated skin sites were scored after 24 and 72 h. Only the non-abraded skin sites were used for the evaluation of the skin irritation potential. The observations on the skin were unremarkable in all animals at any reading time point. Therefore, under the experimental conditions of the study, the test material was not considered to be a skin irritant.

Eye irritation:

CAS 2402-58-6

The potential of Didodecyl fumarate (CAS 2402-58-6) to cause ocular irritation was assessed by a single topical application of 50 µL bulk volume (about 22 mg) of the undiluted test substance to a reconstructed three dimensional human cornea model (EpiOcular TM) (Remmele, 2013). Two EpiOcular TM tissue samples were incubated with the test substance for 90 minutes followed by an 18-hour post-incubation period. Tissue destruction was determined by measuring the reduction of mitochondrial dehydrogenase activity, indicated by reduced formazan production after incubation with a tetrazolium salt (MTT). The formazan production after incubation with a substance treated epidermal tissues is compared to that of negative control tissues. The quotient of the values indicates the relative tissue viability. The EpiOcular TM eye irritation test showed the following results: The test substance is not able to reduce MTT directly. The mean viability of the test substance treated tissues was 82%. Based on the observed results and applying the evaluation criteria it was concluded, that the test substance does not show an eye irritation potential in the EpiOcular TM eye irritation test under the test conditions chosen.

Di-C12-15 Alkyl Fumarate

The potential of Di-C12-15 Alkyl Fumarate to cause eye irritation was assessed in a study similar to OECD guideline 405 (Cantor, 1991). 100 µL of the undiluted test material was placed on the everted lower lid of one eye of each of the six New Zealand White Rabbits used in the study. The upper and the lower lids were gently held together for one second before releasing, to prevent loss of the test material. The untreated eye of each rabbit served as the control. Ocular lesions were evaluated at 24, 48 and 72 h. The observations on the eye were unremarkable in all animals at any reading time point. Therefore, under the experimental conditions of the study, the test material was not considered to be an eye irritant.

 

Conclusion for irritation

In conclusion, the skin irritating properties of the PFAE fumarate category members have been investigated in a validated in vitro study and in an in-vivo skin irritation test in the rabbit indicating no or very low potential for skin irritation. Skin irritating properties of the PFAE fumarate category members have been investigated using the mono-constituent category member Didodecyl fumarate (CAS 2402-58-6) with the shortest fatty alcohol side chain, which is regarded as worst-case approach and with Di-C12-15 Alkyl Fumarate. Therefore, based on the study results with Didodecyl fumarate (CAS 2402-58-6) and with Di-C12-15 Alkyl Fumarate none of the category members of the PFAE fumarate group is considered to be skin irritating.

In conclusion, the eye irritating properties of the PFAE fumarate category members have been investigated in a reliable in vitro study and in an in-vivo eye irritation test in the rabbit indicating no potential for eye irritation. Eye irritating properties of the PFAE fumarate category members have been investigated using the mono-constituent category member Didodecyl fumarate (CAS 2402-58-6) with the shortest fatty alcohol side chain, which is regarded as worst-case approach and with Di-C12-15 Alkyl Fumarate. Therefore, based on the study results with Didodecyl fumarate (CAS 2402-58-6) and with Di-C12-15 Alkyl Fumarate none of the category members of the PFAE fumarate group is considered to be eye irritating.

A detailed reference list is provided in the technical dossier (see IUCLID, section 13) and within CSR.


Justification for selection of skin irritation / corrosion endpoint:
Hazard assessment is conducted by means of read-across. The selected study is the most adequate and reliable study based on the identified similarities in structure and intrinsic properties and overall quality assessment (refer to the endpoint discussion for further details).

Justification for selection of eye irritation endpoint:
Hazard assessment is conducted by means of read-across. The selected study is the most adequate and reliable study based on the identified similarities in structure and intrinsic properties and overall quality assessment (refer to the endpoint discussion for further details).

Justification for classification or non-classification

Based on read-across from category members, the available data on skin and eye irritation do not meet the classification criteria according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and are therefore conclusive but not sufficient for classification.